Covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids functionally active on the CB2 cannabinoid receptor

ABSTRACT

The present invention relates to novel covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids with aminoalcohols of general formula (I) which can usefully be used as agonists of the CB2 cannabinoid receptor and hence as drugs active in pathological conditions which can be controlled by stimulation and/or costimulation of this receptor

This application is a national stage application under 35 U.S.C. § 371of International Application No. PCT/IT99/00207, filed Jul. 7, 1999, andpublished in English as WO 01/04083A1 on Jan. 18, 2001.

This application is a 35 U.S.C. § 371 application.

FIELD OF THE INVENTION

The present invention relates to novel covalent derivatives ofalkanolamides of monocarboxylic and dicarboxylic acids withaminoalcohols which can usefully be used as agonists of the CB2cannabinoid receptor and hence as drugs active in pathologicalconditions which can be controlled by stimulation and/or costimulationof this receptor.

PRIOR ART

Pharmacological effects of the cannabinoids not on the central nervoussystem, such as, for example, vascular and endo-ocular hypotensiveeffects and anti-asthmatic and muscle-relaxant effects have been knownfor some time but, because of the concomitant psychomimetic effects ofthese molecules, their therapeutic use is limited to the treatment ofvery serious pathological conditions such as the cachetic statesassociated with AIDS and, in any case, in particularly controlledclinical situations (Hollister L. E. Pharmacol. Rev. 1986, 38: 1-20).With regard to the multiplicity of the effects of the cannabinoids, thecell and molecular mechanisms upon which these are based are currentlyunder active investigation.

Recent research has demonstrated the functions of the so-called CBcannabinoid receptors. Of these, the CB1 receptor, which was originallyidentified in the central nervous system (SNC), and the CB2 receptor,which is located mainly in peripheral cells of the immune system and hasrecently been found in the T-lymphocytes (Galiegue S. et al. Eur. J.Pharmacol. 1995, 232: 54-61; Munro S. et al. Nature 1993, 365: 61-65;Schatz A. R. et al. Tox. Appl. Pharmacol. 1997, 142: 248-287), have beenstudied in particular.

It is currently considered that the CB2 receptors can mediate theeffects of the cannabinoids on cells of the immune system such as themast cells and the lymphoctyes, by inhibitory modulation of the levelsof pro-inflammatory cytokines which are expressed and secreted in excessby these cells when they are hyperactivated by exposure to tissue toxaeof various kinds (Matsuda L. A. Cit. Rev. Neurobiol. 1997, 11: 143-146).It is therefore considered that functional agonists of the CB2receptor—together with functional agonists of the CB1 receptor whichhave recently also been found at the level of the peripheral nervoussystem (Hohmann A. G. et al. 1997 Abstract Soc. Neurosci. 23: 1954;Richardson J. D. et al 1998 J. Neurosci. 18: 451-457) on cells of theimmune system (Galiegue S. et al. Eur. J. Pharmacol. 1995, 232: 54-61)and on cells of the monocyte-macrophage line (Berdyshev E. V. et al.Eur. J. Pharmacol. 1997, 330: 231-240)—are essentially assigned thefunctions of controlling neuro-immuno-inflammatory processes (RichardsonJ. D. et al. Pain 1998, 75: 111-119; Calignano A. et al. Nature 1998,394: 277-281). In these conditions, it has been shown that synergicfunctional activation of the CB2 receptor and of the CB1 receptor bringsabout maximum control of the neuro-immuno-inflammatory processes,including the hyperalgic phenomenon which frequently accompanies theseprocesses (Calignano A. et al. Nature 1998, 394: 277-281). This synergyof action results from the simultaneous functional activation of the CB1and CB2 receptors which are distributed and/or expressed differently,quantitatively, in tissue components functionally connected with oneanother in a mutual activator-effector relationship, on the basis of thechemical mediators released thereby under agonist stimulus (Calignano A.et al. Nature 1998, 394: 277-281; Levi-Montalcini R. et al. TINS 1996,19: 514-520). It has been shown that the neurokine NGF is a fundamentalmodulator of the neuro-immuno-inflammatory processes triggered by noxaeof various kinds, many of the cell populations being involved in theseNGF-dependent processes for their survival, maturation, differentiationand gene expression (Levi-Montalcini R. et al. TINS 1996, 19: 514-520).It is in fact known that the receptor—known as trk—which has a highaffinity for NGF, is expressed at the level of the peripheral nervoussystem, of the tissue macrophages, and of various cell lines with animmune character such as mast cells, basophilic cells and lymphoctyes.It is also known that these tissue populations also express thecannabinoid receptors CB1 and CB2, although with a differentquantitative pattern (Galiegue S. et al. Eur. J. Pharmacol. 1995, 232:54-61).

Recent results demonstrate a protective role of the CB2 receptor inneurodegenerative processes mediated by excitotoxic amino-acids (SkaperS. D. et al. Proc. Natl. Acad. Sci. U.S.A. 1996, 93: 3984-3989). It hasvery recently also been discovered that the viral protein gp120 of theHIV virus responsible for AIDS can stimulate, by interaction with aspecific “supersite” which is present in a well-preserved region of thevirus and which can thus act as a “superantigene” (Patella V. et al. J.Immunol. 1998, 161: 5647-5655), differential release from the mast cellof specific cytokines—in particular IL4 and IL13—which in turn areresponsible for the maturation and the consequent prevalance of the Th2cells of the immune system, by means of which the virus finds the bestpropagation conditions (Marone G.—Paper to the Congress of the Rome 5-7March 199—Accademia Nazionale dei Lincei). It has also been shown thatthe Th2 cells of the immune system (with particular reference to the C4+clone) express the trk receptor having a high affinity for NGF andthemselves produce NGF as a result of antigenic stimulation (Ehrard P.B. et al. 1993 Proc. Acad. Sci. U.S.A. 90: 10984-10988).

NGF has recently been shown to facilitate and strengthen gene expressionand replication of the HIV virus (Ensoli F. et al. 1994 (Virology, 200:668-676). The levels of NGF neurokine in the serum of patients sufferingfrom AIDS are particularly high and play a part in the progress of thedisease (Pica F. et al. AIDS 1998, 12: 2025-2029). It has recently beenshown that, in conditions of antigenic stimulation, high levels of NGFstrengthen the return, proliferation and tissue differentiation of thecirculating monocytes to macrophages. It is also known that macrophages,by means of suitable chemoreceptors, are tissue reservoirs of the virusand elements of increased tropism for the T-lymphocytes at the sites ofinflammation where the propagation of HIV is greatly facilitated (DiMarzio P. et al. AIDS Res. H. Retrov. 1998, 14: 129-138; Gurwitz D. etal. Mol. Med. Today 1998, 4: 196-200). It has recently been shown that,as a result of antigenic stimulation, endocannabinoids functionallyactive at the CB1 and CB2 receptors modulate differentially theexpression and/or the secretion of proinflammatory cytokine such as, ofexample, IL4, by the monocytes/macrophages (Berdishev E. V. et al. Eur.J. Pharmacol. 1997, 330: 231-240). It is also known that, not only theserum levels, but also the tissue levels of NGF are particularly highduring neuro-immuno-inflammatory processes (Levi-Montalcini R. TINS1996, 19: 514-520). The mast cell is the seat of synthesis, storage andrelease of biologically active NGF which is readily released by the mastcell in response to neurogenic and immunogenic stimuli (Leon A. et al.Proc. Natl. Acad. Sci. U.S.A., 91: 3739-3743). Both the antigenicstimulus represented by the viral protein gp120, and also the neurogenicstimulus represented by the substance P which is released at endotheliallevel in conditions of exposure to the HIV virus (Annunziata P. et alAIDS 1998, 12: 2377-2385) are activators of mast cellhyper-degranulation. In conditions of mast cell hyper-activation, thesensitization of NGF-mediated noxioceptive fibres with an increase inthe levels of substance P released at the level of the peripheral nerveendings is known. It is known that this transmitter release may takeplace orthodromically by axonal reflex, or directly at peripheral levelby means of an endogenic ligand not yet identified (Biro T. et al. J.Invest. Dermatol. 1997, 2: 56-60), owing to the activation of suitablevanilloid receptors—known as VRs—located both at the nerve endings anddirectly on the mast cell (Biro T. et al. Blood 1998, 91: 1332-1340).

In conditions of mast cell hyperactivation by neurogenic and immunogenicstimulus it is also known that the functional activation of the CB2receptor expressed by the mast cell brings about an inhibitorymodulation of the expression and of the secretion of mediators containedtherein (Facci L. et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92:3376-3380). It is also known that the functional activation of the CB1receptor by N-acylvanillin amide molecules reduces the sensitizationinduced by NGF on specific cell lines which coexpress the cannabinoidCB1 receptor (Bisogno T. et al. 1998 Patent No. MI98A002064). It hasalso been shown that this desensitization depends on an inhibitorymodulation of the levels of trk receptor expressed by the specific celllines by the above-mentioned N-acylvanillin amide molecules (De Marzo etal. PNAS 1999, submitted). These N-acylvanillin amide molecules, whichare functional agonists of the CB1 receptor, given their chemicalconstruction, also bring about a functional occupation of the vanilloidreceptor VR which results in a significant strengthening of the NGFdesensitizing effect brought about by the functional activation of theCB1 receptor by means of N-acylvanillin amide (Di Marzo et al PNAS,1999, submitted).

Up to now, neither the activity of molecules functionally agonistic tothe CB2 receptor and of molecules functionally agonistic to the CB1receptor, nor the synergy between these actions at the level of theinteractions between mast cells and the Th2 lymphocytes resulting fromthe stimulation induced by the viral protein gp120 on the mast cell hasbeen known. It has recently been discovered that molecules with anN-acylvanillin amide-type structure which have been found to be capableof acting as functional agonists of the peripheral cannabinoid receptorCB1, have strongly synergic activity with molecules which can act asfunctional agonists of the CB2 receptor expressed by the mast cell(Bisogno T. et al. Italian patent application No. MI98A002064), such asthe molecules discovered by the inventors of this patent.

It is also known that the bioavailability of compounds with poorsolubility both in an aqueous environment and in a lipid environment—anessential element for the purposes of the manifestation of abiologically important effect—is often very limited and variable and inany case such as to constitute a problem to be evaluated with care witha view to their use for therapeutic purposes.

Bioavailability is in fact influenced by various factors and, in thefirst place, by the chemical and physical characteristics of thecompound. The size of the molecule, its charge, its ability to bind toor mix with endogenous compounds such as biliary salts, plasma proteinsor plasma or lymphatic lipids, its stability in the acid pH of thegastric juices are, for example, among the factors which may greatlyinfluence the bioavailability of a compound.

More generally, a certain degree of solibility in an aqueous mediumfavours both their rapid dissolving in the biological fluids and theirsubsequent contact with the cell membranes, through which they thendiffuse as a result of active or passive transportation processes;water-solubility alone, however, does not per se ensure optimalbioavailability.

In order to achieve this object, a compound must also have certaindegree of lipo-solubility to enable it to have an efficient interactionwith the cell plasma membranes which constitute barriers to be crossedby passive diffusion. In fact, since, in the tissues, there is a systemof “solvents” formed by lipids of the cell membranes and by theinterstitial and cytoplasmic liquids, absorption represents an extremelycomplex process which is dependent on the chemical and physicalcharacteristics of the compound; although, on the one hand,lip-solubility favours the passage of the compound through the cellmembranes, on the other hand, this passage is controlled and isdependent proportionally on the concentration of the compound in theaqueous phase, which is also partly correlated with its ability toionize in a physiological medium.

SUMMARY OF THE INVENTION

The inventors of the present patent application have now found thatnovel covalent derivatives of alkanolamides of monocarboxylic anddicarboxylic acids with aminoalcohols can usefully be used as drugs withlipid/water partition coefficients and/or with solubility levels whichare clearly favourable to interaction with biological membranes. In thenovel covalent derivatives of the invention, which have been found to besurprisingly stable, the hydrogen of the alcoholic residue of thealkanolamine is substituted by specific groups which can give a covalentbond with the oxygen.

The novel drugs have been found to be functionally active, as such, onthe CB2 cannabinoid receptor, whereas they are inactive on the CB1receptor. A clear synergy of action between the said compounds andmolecules of an N-acylvanillin amide character which are functionallyactive on the CB1 receptor has also been shown.

A further subject of the present invention is the use of theabove-mentioned novel covalent compounds—alone or in association withN-acylvanillin amide molecules active on the peripheral CB1 receptor—forthe preparation of pharmaceutical compositions for human and veterinaryuse, which are effective for the treatment of the following pathologicalconditions: immuno-inflammatory conditions of various tissue regions,neurodegenerative conditions, conditions due to the spread ofopportunistic viruses, as well as pathological conditions in which anon-psychomimetic effect of cannabinoids is noted; and theircompositions for administration by various routes, including theparental, endovenous, intramuscular and subcutaneous routes, thegastroenteric route, the topical skin and muscous-membrane routes, andtransdermal, ophthalmic and naso-pulmonary routes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula (I):

their enantiomers, diastereoisomers, racemates and mixtures thereof, inwhich:

(a) R1 may be

(1) a linear or branched alkyl radical, saturated or with from 1 to 6double bonds, a monocylic or polycyclic alkyl or alkenyl radical, or anaryl, arylalkyl or heterocyclic radical having one or more heteroatoms,the radicals optionally being substituted with one or more groupsselected from hydroxy, acylamide, keto, nitro, alkoxy, halogen,mercapto, alkylthio, alkyldithio or aryldithio, —N⁺R7R8R9 Z⁻, in whichR7, R8 and R9 are identical to one another or different and may bealkyl, alkenyl or arylalkyl radicals and Z⁻ is the anion of apharmaceutically acceptable organic or inorganic acid;

(2) a group of formula (II):

in which R4 is a linear or branched alkylene radical saturated or withfrom 1 to 6 double bonds, a cycloalkylene or cycloalkylene radical, oran aryl, arylalkyl or heterocyclic diradical with one or moreheteroatoms, the radicals optionally being substituted with one or moregroups selected from hydroxy, acylamide, keto, nitro, alkoxy, halogen,mercapto, alkylthio, alkyldithio, or aryldithio, R5 and R6 have themeanings given below for R2 and R3, respectively, or R5 is a group offormula —Y—OH, where Y has the meaning described below in point (c);

(3) a group of formula (III);

in which R4 has the meanings described above and R10 is hydrogen or alinear or branched alkyl radical or an arylalkyl radical, in which, whenR10 is hydrogen, the resulting carboxylic group may optionally besalified with an organic or inorganic base to form a pharmaceuticallyacceptable salt;

(b) R2 is selected from hydrogen or an alkyl, alkenyl or arylalkylradical;

(c) R3 is a group of formula (IV):

in which:

Y is a linear or branched alkyl radical, optionally substituted with oneor more phenyl groups, possibly substituted with one or more hydroxyand/or alkoxy groups;

X is selected from:

(1) the radical of a cycloalkyl-ether or cycloalkylthio-ether with aring of from 3 to 7 members, possibly substituted and possiblycomprising a second heteroatom;

(2) a group of formula (V):

in which R11 is selected from: a linear or branched alkyl or alkenylradical, possibly containing for 1 to 5 heteroatoms, which may beidentical to one another or different, a monocyclic or polycyclic alkylradical, an arylalkyl radical, an aryl radical or a heterocyclic radicalwhich is aromatic or completely or partially saturated, having one ormore heteroatoms, the radicals optionally being substituted with one ormore groups selected from hydroxy, amino, acylamino, keto, ureide,guanidino, nitro, alkoxy, halogen, —O—PO₃H₂, —O—PO₂H₂, —O— SO₃H, —SO₃H,mercapto, alkylthio, alkyldithio, aryldithio, azido, —NHR9, —NR7R8,—N⁺R7R8R9 Z⁻, in which Z⁻ is the anion of a pharmaceutically acceptableorganic or inorganic acid and R7, and R8 and R9 are as defined above, orR7 and R8 may form, together with the nitrogen atom to which they arefound, a ring of from 3 to 7 members, possibly containing otherheteroatoms selected from oxygen, sulphur and nitrogen, the nitrogenpossibly being substituted by an alkyl, benzyl or hydroxyethyl radical,and in which the basic and acid groups present in the molecule maypossibly be salified with organic or inorganic acids and bases,respectively, to form pharmaceutically acceptable salts;

(3) a group of formula (VI):

in which:

(i) R12 is selected from: a linear or branched alkyl or alkenyl radicalpossibly containing from 1 to 5 heteroatoms which may be identical toone another or different, a monocylic or polycyclic alkyl radical, anarylalkyl radical, an aryl radical or a heterocyclic radical which isaromatic, or completely or partially saturated, having one or moreheteroatoms, the radicals optionally being substituted with one or moregroups selected from hydroxy, amino, acylamino, keto, ureide, guanidino,nitro, alkoxy, —O—C₄H₄—W, halogen, —O—PO₃H₂, —O—PO₂H₂, —O—SO₃H, —SO₃H,mercapto, alkylthio, alkyldithio, aryldithio, azido, —NHR9, —NR7R8,—N⁺R7R8R9 Z⁻, in which Z⁻ is the anion of a pharmaceutically acceptableorganic or inorganic acid, and R7, R8 and R9 are as defined above or R7and R8 may form, together with the nitrogen atom to which they arebound, a ring of from 3 to 7 members, possibly containing otherheteroatoms selected from oxygen, sulphur and nitrogen, possiblysubstituted with an alkyl, benzyl or hydroxyethyl radical, in which W isselected from hydrogen, alkyl, alkoxy, nitro, halogen and hydroxy, andin which the basic and acid groups present in the molecule may possiblybe salified with organic or inorganic acids and bases, respectively, toform pharmaceutically acceptable salts; and

R13 has, independently, the meanings of R12, or may be hydrogen;

(4) a group of formula (VII):

in which R14 is selected from: a linear or branched alkylene orarylalkylene radical, possibly substituted with a hydroxy group or—O—CO—R15, in which R15 is an alkyl, alkenyl or arylalkyl radical, R7,R8 and R9 are as defined above, or R7 and R8 may form, together with thenitrogen atom to which they are bound, a ring of from 3 to 7 members asdefined above, and Z⁻ is a pharmaceutically acceptable inorganic ororganic anion;

(5) a group of formula (VIII):

in which the —SO₃ ⁻ group may be in the ortho, meta or para positionrelative to the keto group, and M⁺ is a pharmaceutically acceptableinorganic or organic cation.

If R2 and R5 are both present on the same molecule, they are preferablyidentical to one another.

If R3 and R6 are both present on the same molecule, they are preferablyidentical to one another.

When R1 is an alkyl radical, it is preferably saturated ormono-unsaturated. It preferably has from 1 to 23 carbon atoms, morepreferably from 11 to 17 carbon atoms and even more preferably from 13to 15 carbon atoms.

When R4 is an alkylene radical, it is preferably saturated ormono-unsaturated. It preferably has from 1 to 20 carbon atoms, even morepreferably from 6 to 14 carbon atoms.

When R7, R8 or R9 is an alkyl or alkenyl radical, it preferably has from1 to 7 carbon atoms. Even more preferably R7, R8 and R9 are identical toone another and are methyl groups.

When R10 is an alkyl radical, it preferably has from 1 to 20 carbonatoms.

When R10 is hydrogen and the resulting carboxyl group is salified, it ispreferably a lithium, sodium potassium, calcium, magnesium, zinc,copper, ammonium, or mono-, di- tri- o tetra-alkyl ammonium salt. In thelatter case, preferred bases for the salification are mono-ethanolamine,N-(2-hydroxyethyl)dimethyl ammonium, choline or amino-acids amongstwhich lysine is preferred.

When R2 is an alkyl or alkenyl group, it preferably has from 1 to 7carbon atoms.

When Y is an alkylene radical, it preferably has from 2 to 20 carbonatoms, even more preferably from 2 to 6 carbon atoms.

When X is a cycloalkyl-ether or a thio-ether, it preferably has a ringwith 5 or 6 members, even more preferably, it is selected fromtetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl,tetrahydrothiofuran-2-yl, 4-methoxytetrahydropyran-2-yl, or1,4-dioxan-2-yl.

When R11 or R12 is an alkyl or alkenyl radical, it preferably has from 1to 25 carbon atoms.

When R11 or R12 is an alkyl or alkenyl radical containing from 1 to 5heteroatoms, these heteroatoms are preferably selected from sulphur,oxygen and nitrogen.

When R7 and R8 form, together with the nitrogen atoms to which they arebound, a ring, the ring preferably has from 5 to 7 members. When thering contains a further nitrogen atom and this nitrogen atom issubstituted by an alkyl radical, it is preferably a methyl or an ethylgroup.

When the —NR12R13 group is the residue of a cyclic amine, this amine ispreferably selected from piperidine, pyrrolidine, morpholine, piperazineand hydroxyethylpiperazine.

When R14 is an alkylene radical, it preferably has from 1 to 10 carbonatoms, more preferably from 2 to 4 carbon atoms.

When R15 is an alkyl or alkenyl radical, it preferably has from 1 to 7carbon atoms.

Z⁻ to preferably selected from chloride, bromide, sulphate, methanesulphonate, hydrogen phosphate, benzene sulphonate, p-toluenesulphonate, acetate, succinate and benzoate.

M⁺ is preferably selected from the following cations: lithium, sodium,potassium, calcium, magnesium, zinc, copper, ammonium, mono-, di-, tri-or tetra-alkyl ammonium, more preferably monoethanol ammonium,N-(2-hydroxyethyl) dimethyl ammonium, or cations of choline or of anamino-acid, preferably lysine.

The term “acylamino” preferably means an acetylamino group.

The term “alkoxy” preferably means a methoxy group.

The term “halogen” preferably means chloro, bromo, iodo or fluoro.

The term “pharmaceutically acceptable acid” preferably means an acidselected from hydrochloric, sulphuric, phosphoric, methane sulphonic,benzene sulphonic, p-toluene sulphonic, acetic, succinic and benzoicacid.

The term “pharmaceutically acceptable base” preferably means a basewhich can form a lithium, sodium, potassium, calcium, magnesium, zinc,copper, ammonium, or mono-, di-, tri- or tetra-alkyl ammonium salt. Inthe latter case the base is preferably monoethanolamine,N-(2)-hydroxyethyl)dimethyl amine, choline or an amino-acid mostpreferably lysine.

The term “arylalkyl radical” preferably means a C₇-C₁₀ arylalkylradical, more preferably a benzyl group.

The term “aryl radical” preferably means a C₆-C₁₀ aryl radical, morepreferably a phenyl group.

The term “heterocyclic radical” preferably means the radical of asaturated, unsaturated or aromatic heterocycle with a ring having 5 or 6members, more preferably selected from tetrahydrofuran, tetrahydropyran,dioxane, pyrrolidine, piperidine, morpholine, thiomorpholine,piperazine, N-methylpiperazine, pyrrole, thiophene, furan, pyrazole,imidazole, thiazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, quinoline, isoquinoline, indole, benzoimidazole,benzothiazole.

The term “cycloalkyl radical” or “cycloalkenyl radical” preferably meansa ring with from 3 to 10 carbon atoms, more preferably 5 to 6 carbonatoms,

PREPARATION OF THE COMPOUNDS OF THE INVENTION

The compounds of the invention may be prepared by reaction anintermediate of formula (Ia):R1-CO-(R2)-Y-OH  (Ia)in which R, R2 and Y are as defined above, with a compound of formulaX′, where X′ is selected from:

in which n is 0 or a whole number between 1 and 4,;

and iodo and R11 is as defined above;

R12—N═C═O or R12R13N-CO-Alg, in which R12, R13 and Alg are as definedabove;

Alg-CO-R14-N⁺R7R8RR9 Z⁻, in which R7, R8, R9, R14, Z⁻ and Alg are asdefined above; and

Alg-CO-Ph-SO₃ ⁻ M⁺, in which M⁺ and Alg are as defined above.

The reaction for the condensation of the intermediates of formula (Ia)with the compounds X′ is generally carried out in an inert solvent andpreferably at a temperature of between −10° C. and the boiling point ofthe solvent used.

An organic base such as, for example, a tertiary amine, or an inorganicbase such as a carbonate or a bicarbonate of an alkali-metal oralkaline-earth metal may also advantageously be used.

Alternatively, when the compound X′ contains a carbonyl group which isintended to react with the hydroxyl group of the intermediate (Ia), thiscarbonyl group may be activated for condensation in known manner, forexample, by transforming it into a hydroxysuccinimide ester or into amixed anhydride, or by carrying out the condensation reaction in thepresence of a condensing agent such as a carbodiimide.

The compounds X′ are known and/or commercially available or may beprepared from known and/or commercially available products in accordancewith methods well known to an expert in the art.

The compounds of formula (Ia) can be prepared as described in EP 0 550008, EP 0 550 006 and EP 0 570 714 which are incorporated herein byreference.

The preparation of the compounds of formula (I) is further described bythe following preparation examples.

EXAMPLE 1 Preparation of N-[2-(ethoxycarbonyl)oxyethyl]hexadecanamide(PEA-EC)

3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was dissolved in75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g ofN-methylmorpholine (11 moles) and 1.19 g of ethyl chloroformate (11moles) were added and the resulting mixture was stirred for a further 3hours at ambient temperature. The mixture was then evaporated to drynessunder vacuum. The residue was taken up with 50 ml of water and extracted3 times with 30 ml of ethyl acetate; the organic phases were washedtwice with 20 ml of water, recombined and evaporated to dryness. Theresidue was crystallized from 30 ml of tert-butylmethyl ether. Thecrystallizate was separated by filtration, washed twice with 5 ml ofcold tert-butylmethyl ether and finally dried under a high degree ofvacuum. The yield of the reaction was 93%.

The product N-[2-ethoxycarbonyl)oxyethyl] hexadecanamide had thefollowing chemical and physical characteristics:

empirical formula: C₂₁H₄₁NO₄ formula weight: 371.57 elementalcomposition: C = 67.88%; H = 11.12%; N = 3.77%, O = 17.22% solubility inwater: slightly soluble solubility in organic 10 mg/ml in ethanol,solvents: ethyl acetate and n-octanol melting point: 71-73° C. TLC in100% ethyl acetate: Rf = 0.62 TLC in heptane/isopropanol/ Rf = 0.70ethyl acetate/water (40:20:50:2):

EXAMPLE 2 Preparation of N-[2-(isobutyloxycarbonyl)oxyethyl]hexadecanamide (PEA-IBC)

3.0 g of N-[2-hydroxyethyl)hexadecanamide (10 mmoles) was dissolved in75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g ofN-methylmorpholine (11 mmoles) and 1.502 g of isobutyl chloroformate (11mmoles) were added and the resulting mixture was stirred for a further 3hours at ambient temperature. The mixture was then evaporated to drynessunder vacuum. The residue was taken up with 50 ml of water and extracted3 times with 30 ml of ethyl acetate; the organic phases were washedtwice with 20 ml of water, recombined and evaporated to dryness. Theresidue was crystallized from 30 ml of cold tert-butylmethyl ether andfinally dried in a high degree of vacuum. The yield of the reaction was50%.

The product, N-[2-(isobutyloxycarbonyl)oxyethyl hexadecanamide had thefollowing chemical and physical characteristics:

empirical formula: C₂₃H₄₅NO₄ formula weight: 399.62 elementalcomposition: C = 69.13%; H = 11.35%; N = 3.50%; O = 16.02% solubility inwater: slightly soluble solubility in 1 mg/ml in ethyl organic solvents:acetate, 10 mg/ml in ethanol, and n-octanol, hot melting point: 65-67°C. TLC in 100% ethyl acetate: Rf = 0.66 TLC in heptane/isopropanol/ Rf =0.73 ethyl acetate/water (40:20:50:2):

EXAMPLE 3 Preparation of N-[3-(ethoxycarbonyl)oxypropyl]hexadecanamide(PPA-EC)

3.14 g of N-(3-hydroxypropyl) hexadecanamide (10 mmoles) was suspendedin 75 ml of tetrahydrofuran (THF) at 45° C. with stirring. 1.11 g ofN-methylmorpholine (11 mmoles) and 1.19 g of ethyl chloroformate (11mmoles) were added and the resulting mixture was stirred for a further 3hours at ambient temperature. The mixture was then evaporated to drynessunder vacuum. The residue was taken up with 50 ml of water and extracted3 times with 30 ml of ethyl acetate; the organic phases were washedtwice with 20 ml of water, recombined and evaporated to dryness. Theresidue was crystallized from 30 ml of tert-butylmethyl ether. Thecrystallizate was separated by filtration, washed twice with 5 ml ofcold tert-butylmethyl ether and finally dried in a high degree ofvacuum. The yield of the reaction was 92%.

The product, (N-[3-)ethoxycarbonyl)oxypropyl] hexadecanamide had thefollowing chemical-physical characteristics:

empirical formula: C₂₂H₄₃NO₄ formula weight: 385.59 elementalcomposition: C = 68.53%; H = 11.24%; N = 3.63%; O = 16.60% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol, organicsolvents: ethyl acetate and n-octanol melting point: 66-68° C. TLC in100% ethyl acetate: Rf = 0.61 TLC in heptane/isopropanol/ Rf = 0.68ethyl acetate/water (40:20:50:2):

EXAMPLE 4 Preparation of N,N¹-bis[2-(ethoxycarbon)oxyethyl] nonandiamide(ADM-EC)

1.37 g of N,N¹-bis(2-hydroxyethyl) nonandiamide (5 mmoles) was dissolvedin 20 ml of anhydrous pyridine. The solution was cooled to 4° C. andsupplemented with 1.19 g of ethyl chloroformate (11 mmoles); theresulting mixture was stirred for 1 hour at 4° C. and then for 3 hoursat ambient temperature. The mixture was then evaporated to dryness undervacuum. The residue was taken up with 50 ml of water and extracted 3times with 30 ml of ethyl acetate; the organic phases were washed twicewith 10 ml of water, recombined and evaporated to dryness. The residuewas crystallized twice, first from 20 ml of ethyl acetate and then from20 ml of tert-butylmethyl ether. The crystallizate was separated byfiltration, washed twice with 5 ml of cold tert-butylmethyl ether, andfinally dried in a high degree of vacuum. The yield of the reaction was88%.

The product, N,N¹-bis[2-(ethoxycarbonyl)oxyethyl] nonandiamide had thefollowing chemical and physical characteristics:

empirical formula: C₁₉H₃₄N₂O₈ formula weight: 418.5 elementalcomposition: C = 54.53%; H = 8.19%; N = 6.69%; O = 30.59% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol, organicsolvents: DMSO melting point: 78-80° C. TLC in 100% ethyl acetate: Rf =0.75 TLC in toluene/ethanol/ Rf = 0.52 acetic acid (63:30:5):

EXAMPLE 5 Preparation of N-[2-benzylaminocarbonyl)oxyethyl]hexadecanamide (PEA-BCM)

3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 moles) was suspended in60 ml of anhydrous toluene; the mixture was stirred and heated withrefluxing of the solvent into anhydrous 4 Å molecular sieves withrecycling. 3.0 ml of benzylisocyanate was added and the resultingmixture was heated with refluxing for 6 hours. 2 ml of methanol was thenadded and the heating to temperature was continued for a further hour.The product crystallized as a result of cooling to ambient temperature.The crystallizate was separate by filtration, washed twice with 5 ml ofcold toluene and finally dried under a high degree of vacuum. The yieldof the reaction was 94%.

The product, N-[2-benzylaminocarbonyl)oxyethyl]hexadecanamide had thefollowing chemical and physical characteristics:

empirical formula: C₁₆H₄₄N₂O₃ formula weight: 432.65 elementalcomposition: C = 72.18%; H = 10.25%; N = 6.48%; O = 11.09% solubility inwater: slightly soluble solubility in 10 mg/ml in ethyl organicsolvents: acetate and n-octanol, hot melting point: 126.5-128.5° C. TLCin 100% ethyl acetate: Rf = 0.47 TLC in heptane/isopropanol/ Rf = 0.65ethyl acetate/water (40:20:50:2):

EXAMPLE 6 Preparation of N-[2-(ethoxycarbonylmethyl)aminocarbonyl]oxyethyl] hexadecanamide (PEA-EGC)

3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was suspended in60 ml of anhydrous toluene; the mixture was stirred and heated withrefluxing of the solvent onto 4 Å molecular sieves with recycling. 3. 0g of ethyl isocyanate acetate was added and the resulting mixture washeated with refluxing for 6 hours. The mixture was then cooled to 4° C.The crystallizate formed was separated by filtration and crystallizedfrom 20 ml of toluene, cold; it was then separated again by filtration,washed twice with 5 ml of cold toluene and finally dried in a highdegree of vacuum. The yield of the reaction was 92%.

The product, N-[2-[(ethoxycarbonylmethyl)aminocarbonyl]oxyethyl]hexadecanamide had the following chemical and physical characteristics:

empirical formula: C₂₃H₄₄N₂O₅ formula weight: 428.62 elementalcomposition: C = 64.45%; H = 10.35%; N = 6.54%; O = 18.66% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol, organicsolvents: n-octanol, hot melting point: 105-106° C. TLC in 100% ethylacetate: Rf = 0.40 TLC in heptane/isopropanol/ Rf = 0.58 ethylacetate/water (40:20:50:2):

EXAMPLE 7 Preparation of N-[2-[(2-piperidinoethoxy)carbonyl]oxyethyl]hexadecanamide (PEA-PEC)

3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was dissolved in60 ml of tetrahydrofuran (THF) in an anhydrous N₂ atmosphere. 1.11 g ofN-methylmorpholine (11 mmoles) was added and the mixture was furthersupplemented with 1.88 g of (2-bromoethyl) chloroformate (10 mmoles)slowly, dropwise, over a period of 30 minutes. The resulting mixture waskept at ambient temperature with stirring for a further 3 hours and thenevaporated to dryness. The residue was taken up with 20 ml of water andextracted 3 times with 20 ml of ethyl acetate. The organic phases werewashed twice with 20 ml of water, recombined and evaporated to dryness.The residue was taken up with 50 ml of anhydrous tetrahydrofuran andsupplemented with 1.70 g of piperidine (20 mmoles). The mixture washeated to reflux with stirring for 6 hours; it was then cooled toambient temperature and supplemented with 20 ml of water and 60 ml ofethyl acetate. The aqueous phase was discarded the organic phase waswashed with 10 ml of cold 2M NH₃ solution and then with 20 ml of coldwater. The aqueous phases were discarded and the organic phase wasevaporated to dryness. The residue was crystallized from 30 ml of ethylacetate, cold. The crystallizate was separated by filtration, washedtwice with 5 ml of cold ethyl acetate and finally dried under a highdegree of vacuum. The yield of the reaction was 89%.

The product, N-[2-[(2-piperidinoethoxy)carbonyl]oxyethyl] hexadecanamidehad the following chemical and physical characteristics:

empirical formula: C₂₆H₅₀N₂O₄ formula weight: 454.70 elementalcomposition: C = 68.68%; H = 11.08%; N = 6.16%; O = 14.08% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol, organicsolvents: melting point: 65-67° C. TLC in 100% ethyl acetate: Rf = 0.05TLC in toluene/ethanol/ Rf = 0.11 acetate acid (65:30:5):

EXAMPLE 8 Preparation of N-[2-[(2-piperidinoethoxy)carbonyl]oxyethyl]hexadecanamide methane sulphonate (PEA-PECMetS)

4.5 g of N-[2-[(2-piperidinoethoxy)carbonyl]oxyethyl] hexadecanamide wasdissolved in 50 ml of anhydrous ethanol and supplemented with 0.96 g ofmethane sulphonic acid, cold. The mixture was evaporated to dryness andthe residue was taken up with 100 ml of distilled water. The solutionwas frozen and lyophilized.

The product, N-[2-[(2-piperidinoethoxy)carbonyl]oxyethyl] hexadecanamidemethane sulphonate had the following chemical and physicalcharacteristics:

empirical formula: C₂₇H₅₄N₂O₇S formula weight: 550.82 elementalcomposition: C = 58.88%; H = 9.88%; N = 5.09%; O = 20.23% S = 5.82%solubility in water: 10 mg/ml solubility in 10 mg/ml in ethanol organicsolvents: and DMSO melting point: n.d. TLC in toluene/ethanol/ Rf = 0.11acetic acid (65:30:5):

EXAMPLE 9 Preparation of the tetrahydrofuranyl ether ofN-(2-hydroxyethyl) hexadecanamide (PEA-THF)

3.0 g of N-(2-hydroxyethyl) hexadecanamide (10 mmoles) was suspended in20 ml of 2,3-dihydrofuran and cooled to 4° C. The mixture wassupplemented with 200 mg of pyridinium methane sulphonate withcontinuous stirring and then heated to 50° C. for 60 minutes. Themixture was brought to ambient temperature, supplemented with 50 ml ofethyl acetate and extracted twice with 10 ml of cold water. The aqueousphases were separated and discarded and the organic phase was evaporatedto dryness under vacuum. The residue was crystallized from 20 ml oftert-butylmethyl ether. The crystallizate was separated by filtration,washed twice with 4 ml of cold tert-butylmethyl ether and finally driedunder a high degree of vacuum. The yield of the reaction was 90%.

The product, the tetrahydrofuranyl ether of N-(2-hydroxyethyl)hexadecanamide had the following chemical and physical characteristics:

empirical formula: C₂₂H₄₃NO₃ formula weight: 369.59 elementalcomposition: C = 71.50%; H = 11.73%; N = 3.97%; O = 12.99% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol organicsolvents: and DMSO melting point: 63-65° C. TLC in 100% ethyl acetate:Rf = 0.41 TLC in heptane/isopropanol/ Rf = 0.62 ethyl acetate/water(40:20:50:2):

EXAMPLE 10 Preparation of the tetrahydrofuranyl ether ofN,N¹-bis(2-hydroxyethyl) nonandiamide (ADM-THF)

1.37 g of N,N¹-bis (2-hydroxyethyl) nonandiamide (5 mmoles) wassuspended in 6ml of 2,3-dihydrofuran. The mixture was stirred at 4° C.and supplemented with 60 mg of pyridinium methane sulphonate; themixture was then heated to 50° C. for 60 minutes. The mixture was thencooled to ambient temperature, supplemented with 30 ml of ethyl acetateand extracted twice with 5 ml of cold water. The aqueous phases wereseparated and discarded and the organic phases were evaporated todryness under vacuum. After thorough drying in a high degree of vacuum,the residue was dispersed cold with 5 ml of tert-butylmethyl ether. Thepowdery solid thus obtained was separated by filtration, washed twicewith 2 ml of cold tert-butylmethyl ether and finally dried under a highdegree of vacuum. The yield of the reaction was 94%.

The product, the tetrahydrofuranyl ether of N,N¹-bis(2-hydroxyethyl)nonandiamide had the following chemical and physical characteristics:

empirical formula: C₂₁H₃₈N₂O₆ formula weight: 414.55 elementalcomposition: C = 60.84%; H = 9.24%; N = 6.76%; O = 23.16% solubility inwater: 10 mg/ml in water solubility in 10 mg/ml in ethanol organicsolvents: and DMSO melting point: 58-60° C. TLC in acetonitrile/water(9:1) Rf = 0.52 TLC in toluene/ethanol/ Rf = 0.44 acetic acid (65:30:5):

EXAMPLE 11 Preparation of the tetrahydropyranyl ether ofN-(2-hydroxyethyl) hexadecanamide (PEA-THP)

3.0 g of N-bis(2-hydroxyethyl) hexadecanamide (10 mmoles) was suspendedin 20 ml of 3,4-dihydropyran and cooled to 4° C. 200 mg of pyridiniummethane sulphonate was added and the mixture was stirred at 50° C. for60 minutes. The mixture was then brought to ambient temperature,supplemented with 50 ml of ethyl acetate and extracted twice with 10 mlof cold water. The aqueous phases were separated and discarded and theorganic phase was evaporated to dryness with rotation. The residue wastaken up with 20 ml of petroleum ether and crystallized. Thecrystallizate was separated by filtration, washed twice with 4 ml ofcold petroleum ether and finally dried in a high degree of vacuum. Theyield of the reaction was 93%.

The product, the tetrahydropyranyl ether of N-(2-hydroxyethyl)hexadecanamide had the following chemical and physical characteristics:

empirical formula: C₂₃H₄₅NO₃ formula weight: 383.62 elementalcomposition: C = 70.01%; H = 11.824%; N = 3.65%; O = 12.51% solubilityin water: slightly soluble solubility in 10 mg/ml in ethyl organicsolvents: acetate and n-octanol melting point: 52.5-54.5° C. TLC in 100%ethyl acetate Rf = 0.43 TLC in heptane/isopropanol/ Rf = 0.65 ethylacetate/water (40:20:50:2):

EXAMPLE 12 Preparation of the tetrahydropyranyl ether ofN,N¹-bis(2-hydroxyethyl) nonandiamide (ADM-THP)

1.37 g of N,N¹-bis(2-hydroxyethyl) nonandiamide (5 mmoles) was suspendedin 6 ml of 3,4-dihydropyran. The mixture was stirred at 4° C. andsupplemented with 60 mg of pyridinium methane sulphonate; the mixturewas then heated to 50° C. for 60 minutes. The mixture was cooled toambient temperature, supplemented with 30 ml of ethyl acetate andextracted twice with 5 ml of water. The aqueous phases were separatedand discarded and the organic phase was evaporated to dryness undervacuum. After thorough drying in a high degree of vacuum, the residuewas dispersed cold with 5 ml of tert-butylmethyl ether. The powderysolid thus obtained was separated by filtration, washed twice with 2 mlof tert-butylmethyl ether and finally dried in a high degree of vacuum.The yield of the reaction was 92%.

The product, the tetrahydropyranyl ether of N,N¹-bis(2-hydroxyethyl)nonandiamide had the following chemical-physical characteristics:

empirical formula: C₂₃H₄₂N₂O₆ formula weight: 442.60 elementalcomposition: C = 62.42%; H = 9.57%; N = 6.33%; O = 21.69% solubility inwater: 10 mg/ml solubility in 10 mg/ml in ethanol organic solvents: andDMSO melting point: 55-57° C. TLC in acetonitrile (9:1): Rf = 0.56 TLCin toluene/ethanol/ Rf = 0.51 acetic acid (65:30:5):

EXAMPLE 13 Preparation of N-[2-(ethoxycarbonyl)oxyethyl] oleoylamide(OEA-EC)

3.3 g of N-(2-hydroxyethyl) oleoylamide (10 mmoles) was dissolved in 75ml of tetrahydrofuran (THF) with stirring. The solution was cooled to 4°C. and supplemented with 1.11 g of N-methyl morpholine (11 mmoles) and1.19 g of ethyl chloroformate (11 mmoles). The resulting mixture waskept at 4° C. for 30 minutes with continuous stirring and then for afurther 24 hours at ambient temperature. The mixture was then evaporatedto dryness under vacuum. The residue was taken up with 50 ml of waterand extracted 3 times with 30 ml of ethyl acetate; the organic phaseswere washed twice with 20 ml of water, recombined and evaporated todryness. The residue was purified by preparative chromatography onsilica gel with the use of a mixture of ethyl acetate and hexane in aratio of 50:50, as the eluent. The fractions containing the product wererecombined and evaporated to dryness. The oily residue was dried under ahigh degree of vacuum (yield 80%).

The product, N-[2-(ethoxycarbonyl)oxyethyl]oleoylamide had the followingchemical and physical characteristics:

empirical formula: C₂₃H₄₃NO₄ formula weight: 397.40 elementalcomposition: C = 69.48%; H = 10.90%; N = 3.52%; O = 16.10% solubility inwater: slightly soluble solubility in 10 mg/ml in ethanol, organicsolvents: ethyl acetate and n-octanol TLC in 100% ethyl acetate: Rf =0.63 TLC in heptane/isopropanol/ Rf = 0.69 ethyl acetate/water(40:20:50:2):

Chemical and physical characteristics of the compounds of the invention

The chemical and physical characteristics of the derivatives accordingto the invention were evaluated by quantitative according to theinvention were evaluated by quantitative measurement of the lipid/waterpartition parameter.

A useful parameter for evaluating the properties of a compound inrelation to its possible absorption is in fact constituted by thecoefficient of partition between the lipid phase and the aqueous phase,which is considered to be an expression of its lipophilicity and itsdegree of hydrophilicity. In general, it is commonly accepted that thegreater the lipid/water partition coefficient is, the greater is theaffinity for the cell membranes and hence the greater and quicker is theabsorption. For the purpose of evaluating the characteristics of thederivatives of the invention, the partition parameter RM between thelipid and the aqueous phase, extrapolated from thin-film partitionchromatography, was calculated; this parameter is commonly used toevaluate the lipophilic characteristics of compounds (Tomlinson E. J.Chromatogr. 1975, 113, 1) and is commonly used, for example, for localanaesthetics, in which a correlation has been shown between thisparameter and biological activity (Bachrata M. et al. J. Chromatogr.1979, 171, 29-36).

The partition parameter RM between the lipid phase and the aqueous phasewas calculated both for the derivatives and for the non-substitutedalkanolamides, from the Rf value obtained by thin-film chromatography onsilica gel (particles of 2-2.5 μmoles, mean porosity 60 Å, thickness0.25 mm on glass plate) in accordance with the formula:RM=log (1/Rf−1)and the ΔRM was obtained from the difference between the RM coefficientsof the derivative and of the corresponding alkanolamide. The resultsobtained were as follows:

TABLE I compound Example solvent 1 solvent 2 No. RF RM ΔRM RF RM ΔRM 10.62 −0.213 −1.001 0.70 −0.368 −0.403 2 0.66 −0.288 −1.076 0.73 −0.432−0.467 5 0.47 0.052 −0.736 0.65 −0.269 −0.304 6 0.40 0.176 −0.612 0.58−0.140 −0.175 7 0.05 1.28 0.49 — — — 9 0.41 0.158 −0.630 0.62 −0.213−0.247 11 0.43 0.122 0.666 0.65 −0.269 −0.304 3 0.61 −0.194 −1.020 0.68−0.327 −0.397 13 0.63 −0.231 −0.984 0.69 −0.347 −0.365 4 0.75 −0.477−0.866 0.52 −0.035 −0.723 10 0.52 −0.035 −0.424 0.44 0.105 −0.584 120.56 −0.105 −0.494 0.51 −0.017 −0.706 Solvent 1: 100% ethyl acetateSolvent 2: heptane:isopropanol:ethyl acetate:H2O 40:20:50:2 Solvent 3:acetonitrile:H2O 9:1 Solvent 4: toluene:ethanol:acetic acid 65:30:5It can be seen from the results obtained that the covalent derivativesof the present invention surprisingly have a decidedly more markedlipophilic nature than the starting alkanolamides and hence more rapidabsorption both at gastrointestinal level and topically. It should alsobe noted that, as already described in the prior art, substitutions onthe alcoholic hydroxyl with carbamates and carbonates have already beeninvestigated in order to improve the water-solubility of “hinderedalcohols” but the resulting derivatives were found to be highly unstable(Safadi M. et al. Pharm. Res. 1993, 10, 1350-1355). The derivativesobtained by the invention, on the other hand, have been found,surprisingly, to possess very good lipo-solubility characteristics andhave been found to be substantially stable. Water-solubility may,however, also be achieved by introducing substituents which can beionized and which can thus be salified; compounds with good solubilityin aqueous solvents are thus produced, this characteristic beingparticularly important both for ensuring absorption and for theadministration of the pharmacological agent in aqueous solution, forexample, by a parenteral route.

The demonstrated ability to substitute the hydrogen of the alcoholicresidue of the alkanolamide with novel substituents which can givestable covalent bonds with the oxygen forms part of the presentinvention.

BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION

The compounds of the invention were tested with the use of biochemicaltests in vitro which are described in the following biological examples.The compounds are identified on the basis of the number of the examplegiven in the preceding chemical examples section above.

Example A

Effect of alkanolamide molecules on the binding of the synthetic ligandsof the CB2 and CB1 cannabinoid receptors, respectively.

Rat RBL-2H3+ leukemic basophilic cells, which selectively express thecannabinoid CB2 receptor, and mouse N18TG2 neuroblastoma cells whichselectively express the CB1 cannabinoid receptor were used. The cellswere cultivated as described above (Facci L. et al. (1995) Proc. Natl:Acad: Sci. U.S.A. 92:: 3376-3380; Bisogno T. et al. 1997 J. Biol. Chem.,272: 3315-3323). WIN 55,212.2 was used as the selectively agonistsynthetic ligand for the CB2 receptor.

SR141716A was used as the selective antagonist for the CB1 receptor.

HU-210 was used as the selective antagonist for the CB2 receptor.

[³H]SR141716A (55 Ci/mmol) was supplied by Amersham; [³H]WIN55,212-2 (43Ci/mmol) was supplied by NEN. The binding tests were performed withmembranes of the cells resuspended in 50 mMol Tris pH 7.0 buffer; 2.5mMol MgCl₂, 0.8 mMol EDTA; 0.05% bovine serum albumin (BSA); 0.01%ethanol, in the presence of 100 μM of phenyl-methyl-sulphonyl fluoride(PMSF-Sigma), with the use, of 300 pM of [³H]SR141716A and of[³H]WIN55,212-2, respectively, as the ligand.

The membranes were incubated for 90′ at 30° C. and filtered on glassmicrofibre filters (GFC-Whatman) and the radioactivity was detected byliquid scintillation. The specific binding was calculated with the useof either 10 μM SR141716A or 10 μM HU-210.

The Ki values were calculated by Chang-Prusoff's equation and expressedas concentration μM.

TABLE II CB2 receptor CB1 Receptor RBL-2H3 + cells N18TG2 cells Lig.[³H]WIN55, 212-2 Lig. [³H]SR141716A compounds Ki (μM) Ki (μM) phenylbutazone >15 >15 Comp. Example 4 0.002 ± 0.0009 >15 Comp. Example 60.001 ± 0.0008 >15 Comp. Example 1 0.006 ± 0.0018 >15 Comp. Example 70.009 ± 0.0025 >15

Example B

Effect of alkanolamide molecules on the stimulation of cyclic AMP (cAMP)by forskolin.

The tests were performed with the aim of checking whether the binding ofthe molecules of the present invention to the CB2 receptor hasfunctional significance.

It is in fact known that the function activation of the CB2 receptorbrings about, at intracellular level, inhibition of the enzymaticactivity of adenylate cyclase and a reduction in the levels of thesecond-messenger cAMP, resulting in an increase in the conductance ofthe channels to potassium and an inhibition of proteic phosphorylation(Childers S. R. et al. Biochem. Parmacol. 1996, 52: 819-827).

The dosages of cAMP were performed on RBL-2H3+ cells flowing together inPetri dishes with six wells (Falcon); the cells were stimulated for 10′at 37° C. with 1 μM of forskolin (Fluka) in 400 μl of medium withoutserum, containing 20 mM HEPES, 0.1 mg/ml BSA and 0.1 mM1-methyl-3-isobutyl xanthine (Sigma) and either ethanol or alkanolamidemolecules with or without the addition of HU-210. After incubation, thecells were extracted and the levels of cAMP were evaluated with asuitable Amersham kit in accordance with the producer's method. The datawere expressed in IC50 μM.

TABLE III Compounds Example No. IC50 μM 4 1.8 4 + HU-210 (0.5 μM) >20 61.9 6 + HU-210 (0.5 μM) >20The covalent derivatives of the invention can thus usefully be used forthe treatment of inflammatory processes, and also those with hyperalgiccomponents—both with a neurogenic basis and with an immunogenicbasis—associated with immuno-inflammatory pathological conditions, andalso autoimmune conditions, with neurodegenerative conditions associatedwith excitotoxic processes, as well as for conditions in which anon-psychomimetic effect of cannabinoids is known, all effects beingattributable to an activity mediated by the CB2 receptor; amongst these,the following pathological conditions are mentioned by way ofnon-limiting example: neurological conditions such as, for example,multiple sclerosis, peripheral neuropathies—both somatic andautonomic—with various aetiologies, anoxic-ischaemic strokes andthromboses, cranial and spinal trauma, neurodegenerative conditions(AIDS—complex demetia, senile dementia, Alzheimer's syndrome, Parkinsonssyndrome, amyotrophic lateral sclerosis), epilepsy, transitory ischaemicattacks (TIA) Huntington's chorea, retinal conditions with ananoxic-ischaemic basis, and also conditions secondary to glaucoma,headaches; viral conditions with particular reference to conditionssustained by the propagation of so-called opportunistic viruses (suchas, for example, the HIV virus), that is, viruses which can use thedefense mechanisms of the organism itself to render its own propagationpossible; skin conditions such as, for example psoriasis, atopicdermatitis and allergic dermatitis, lichen planus, dermatomyositis,scleroderma, pemphigus, pemphigoids, epidermolysis bullosa, discoid andsystemic lupus erythematosus, heliodermatitus, indolent ulcers,hypertrophic scars, keloids, vulvar vestibulitis; conditions of themucous membrane, such as, for example, oral lichen planus, stomatitis,acute and recurrent vaginitis, balanitis and balanoposthitis, and alsoconditions connected with inflammatory states of the accessory sexglands (prostate, vesical, seminal, etc.); respiratory conditions suchas, for example, asthma, interstitial pulmonary fibrosis, allergicrhinitis; gastrointestinal conditions such as, for example, chronicinflammations of the mucosa, ophthalmic conditions such as, for exampleuveitis, uveoretinitis, Sjogren's syndrome, keratoconjunctivitis sicca,corneal ulcers, allergic and infectious conjunctivitis and giantpapillary conjunctivitis, scar pemphigoids; joint conditions, such as,for example rheumatic arthritis, rheumatoid arthritis, arthritisconnected with psoriasis or with lupus, chronic arthritis and arthrosis,chondrodegeneration of traumatic, infectious and degenerative origin;cardiovascular conditions such as, for example, re-stenosis afterangioplasty, atherosclerosis and cardiac ischaemic attacks, recurrenceof episodes of infarction; specifically veterinary conditions such as,for example, conditions of the intervertebral disks in dogs and inhorses, Stringhalt's syndrome, and laminitis in horses, skin, joint orconnective-tissue conditions in horses, in dogs and in cats.

For the treatment of the above-mentioned conditions, the derivatives ofthe present invention may be administered by a parenteral systemic route(endovenously, intramuscularly, subcutaneously), a rectal route, or anoral route but also by a topical route (dermal and mucosal, ophthalmic,naso-pulmonary) and by a transdermal route. The dosages in which theyare used may vary according to the administration route and to theseriousness of the disease and of the general condition of the patient.In any case, the expected therapeutic dosages are from 0.1 mg/die to 1g/die for a period of between one week and three months of continuedadministration. According to the chronic nature of the condition, thetreatment may be repeated in various cycles.

The derivatives according to the invention may be administered inpharmaceutical compositions with excipients or diluents which areacceptable from the point of view of pharmaceutical use and are suitablefor the purposes and in any case are such as to permit and/or tooptimize adsorption by the selected administration route. In particular,formulations in solution or suspension and also those produced with theuse of preliminary micronization techniques and/or co-micronization withother active ingredients or with excipients for parental administrationare envisaged; for the ophthalmic route, liquid forms as eye lotions andsolid or semisolid forms as inserts, gels and ointments may be selected,and for oral administration they may be in the form of capsules,tablets, powders and pellets and also in gastroresistant formulationsand may also be produced with the use of preliminary microencapsulation,liposomization and micellization techniques. For the topical routes,including the transdermal route, formulations as suppositories,micro-enemas, creams, ointments, sprays, gels, foams, dressings ofvarious thicknesses and patches may be used. All of the possiblepharmaceutical forms indicated for the various administration routes mayalso be formulated with excipients or technological processes suitablefor producing fast-release or slow-release medicaments which thederivatives of the invention.

It has also been found that the compounds of the present invention mayalso be used effectively as cosmetic ingredients having the function ofconditions and/or rheological additives. A further subject of thepresent invention is therefore the use of the compounds of formula (I)in cosmetics.

The invention is further described by the following non-limitingexamples thereof; it is also possible to use other formulations producedwith other ingredients and with other excipients for these purposes.

EXAMPLE 14 Ampoules for Injection

Compound of Example 8 20 mg sodium chloride 17 mg water for injectablesto make up to 2 ml

EXAMPLE 15 Lyophilized Ampoules

Each lyophilized ampoule contains: Compound of Example 6 30 mg(co-micronized with mannitol) N-(4-hydroxy-3-methoxybenzyl)oleoyl amide30 mg (co-micronized with mannitol) mannitol 80 mg each solvent ampoulecontains: soya lecithin 40 mg water for injectables to make up to 2 ml

EXAMPLE 16 Tablets

Compound of Example 4, micronized 100 mg  lactose 100 mg  maize starch70 mg  talc 8 mg magnesium stearate 4 mg carboxymethyl cellulose 8 mg

EXAMPLE 17 Capsules

Compound of Example 7 100 mg  N-(4-hydroxy-3-methoxybenzyl) 50 mgpalmitoylamide maize oil 150 mg  gelatine FU 70 mg glycerol FU 30 mgtitanium dioxide (E171) 0.5 mg  erythrosin (E127)  1 mg

EXAMPLE 18 Eye Lotion

Compound of Example 8 2 mg benzalkonium chloride 1 mg monobasic sodiumphosphate hydrate 41 mg dibasic sodium phosphate.12H₂O 249.5 mg sodiumedetate 10 mg bi-distilled water to make up to 10 ml

EXAMPLE 19 Ophthalmic Ointment

Compound of Example 4, micronized 100 mg viscous white Vaseline to makeup to 100 g

EXAMPLE 20 Skin Cream

Compound of Example 4 100 mg hyaluronic acid 200 mg sorbitanmonostearate 500 mg polyoxyethylene sorbitan monostearate 3 g stearicacid 3 g Vaseline oil 15 g methyl ester of para-oxybenzoic acid 200 mgethyl ester of para-oxybenzoic acid 50 mg demineralized water to make upto 100 g

EXAMPLE 21 Vaginal Gel

Compound of Example 7 150 mg N-(4-hydroxy-3-methoxybenzyl)- 100 mgpalmitoylamide hyaluronic acid, sodium salt 100 mg sodium alginate 2.5 gglycerol 5 g Bronopol 300 mg demineralized water to make up to 100 g

EXAMPLE 22 Lotion for Trichological Use

Compound of Example 4 300 mg propylene glycol 25 g ethyl alcohol 50 gdemineralized water to make up to 100 g

EXAMPLE 23 Gel for Dental Use

Compound of Example 12 300 mg hyaluronic acid 200 mg (titrated inbio-binding epitope) carbomer 300 mg sorbitol 20 g methyl p-oxybenzoate200 mg ethyl p-oxybenzoate 50 mg peppermint flavouring 1 g demineralizedwater to make up to 100 g

1. Compounds of the general formula (I):

their enantiomers, diastereomers, racemates and mixtures thereof, inwhich: (a) R₁ is (1) a linear or branched alkyl radical, saturated orwith from 1 to 6 double bonds, a monocyclic or polycyclic alkyl oralkenyl radical, or an aryl, arylalkyl or heterocyclic radical havingone or more heteroatoms, the radicals optionally being substituted withone or more groups selected from hydroxy, acylamide, keto, nitro,alkoxy, halogen, —N⁺R₇R₈R₉ Z⁻ in which R₇, R₈ and R₉ are identical toone another or different and may be alkyl, alkenyl or arylalkyl radical,and Z⁻ is the anion of a pharmaceutically acceptable organic ininorganic acid; (2) a group of formula (II):

in which R₄ is a linear or branched alkylene radical saturated or withfrom 1 to 6 double bonds, a cycloalkylene or cycloalkenylene radical, oran aryl, arylalkyl or heterocyclic diradical with one or moreheteroatoms, the radicals optionally being substituted with one or moregroups selected from hydroxy, acylamide, keto, nitro, alkoxy, halogen,R₅ and R₆ have the meanings given below for R₂ and R₃, respectively, orR₅ is a group of formula —Y—OH, where Y has the meaning described belowin point (c); or (3) a group formula (III):

in which R₄ has the meanings described above and R₁₀ is hydrogen or alinear or branched alkyl radical or an arylalkyl radical, in which, whenR₁₀ is hydrogen, the resulting carboxylic group may optionally besalified with an organic or inorganic base to form a pharmaceuticallyacceptable salt; (b) R₂ is selected from hydrogen or an alkyl, alkenylor arylalkyl radical; (c) R₃ is group of formula (IV):

in which: Y is a linear or branched alkyl radical, optionallysubstituted with one or more phenyl groups, possibly substituted withone or more hydroxy and/or alkoxy groups; X is selected from: (1) theradical of a cycloalkyl-ether with a ring of from 3 to 7 members,possibly substituted and possibly comprising a one or two heteroatom;(2) a group of formula (V):

in which R₁₁ is selected from: a linear or branched alkyl or alkenylradical, possibly containing from 1 to 5 heteroatoms, which may beidentical to one another or different, a monocyclic or polycyclic alkylradical, an arylalkyl radical, an aryl radical or a heterocyclic radicalwhich is aromatic or completely or partially saturated, having one ormore heteroatoms, the radicals optionally being substituted with one ormore groups selected from hydroxy, amino, acylamino, keto, ureide,guanidino, nitro, alkoxy, halogen, —O—PO₃H₂, —O—PO₂H₂, —O—SO₃H, —SO₃H,azido, —NHR₉, —NR₇R₈, —N⁺R₇R₈R₉ Z⁻, in which Z⁻ is the anion of apharmaceutically acceptable organic or inorganic acid and R₇, R₈ and R₉are as defined above or R₇ and R₈ may form, together with the nitrogenatom to which they are bound, a ring of from 3 to 7 members, possiblycontaining other heteroatoms selected from oxygen and nitrogen, thenitrogen possibly being substituted by an alkyl, benzyl or hydroxyethylradical, and in which the basis and acid groups present in the moleculemay possibly be salified with organic or inorganic acids and bases,respectively, to form pharmaceutically acceptable salts; (3) a group offormula (VI):

in which: (i) R₁₂ is selected from: a linear or branched alkyl oralkenyl radical possibly containing from 1 to 5 heteroatoms which may beidentical to one another or different, a mono- or polycyclic alkylradical, an arylalkyl radical, an aryl radical or a heterocyclic radicalwhich is aromatic or completely or partially saturated, having one ormore heteroatoms, the radicals optionally being substituted with one ormore groups selected from hydroxy, amino, acylamino, keto, ureide,guanidino, nitro, alkoxy, —O—C₆H₄—W, halogen, —O— PO₃H₂, O—PO₂H₂, azido,—NHR₉, —NR₇R₈, —N⁺R₇R₈R₉ Z⁻, in which Z⁻ is the anion of apharmaceutically acceptable organic or inorganic acid, and R₇, R₈ and R₉are as defined above or R₇ and R₈ may form, together with the nitrogenatom to which they are bound, a ring of from 3 to 7 members, possiblycontaining other heteroatoms selected from oxygen, sulphur and nitrogen,possibly substituted with an alkyl, benzyl, or hydroxyethyl radical, inwhich W is selected from hydrogen, alkyl, alkoxy, nitro, halogen, andhydroxy, and in which the basic and acid groups present in the moleculemay possibly be salified with organic or inorganic acids and bases,respectively, to form pharmaceutically acceptable salts; R₁₃ has,independently, the meanings of R₁₂, or may be hydrogen; (4) a group offormula (VII):

in which R₁₄ is selected from: a linear or branched alkylene orarylalkylene radical, possibly substituted with a hydroxy group or—O—CO—R₁₅, in which R₁₅ is an alkyl, alkenyl or arylalkyl radical, R₇,R₈ and R₉ are as defined above, or R₇ and R₈ may form, together with thenitrogen atom to which they are bound, a ring of from 3 to 7 members asdefined above, and Z⁻ is a pharmaceutically acceptable inorganic ororganic anion; and (5) a group of formula (VIII):

in which the —SO₃ ⁻ group may be in the ortho, meta or para positionrelative to the keto group, and M⁺is a pharmaceutically acceptableinorganic or organic cation.
 2. A compound according to claim 1, whereinR₂ and R₅ are identical to one another.
 3. A compound according to claim1, wherein R₃ and R₆ are identical to one another.
 4. A compoundaccording to claim 1, wherein R₁ is a saturated or mono-unsaturatedalkyl radical with from 1 to 23 carbon atoms.
 5. A compound according toclaim 1, wherein R₄ is a saturated or mono-unsaturated alkylene radicalwith from 1 to 20 carbon atoms.
 6. A compound according to claim 1,wherein R₇, R₈ and R₉ are alkyl or alkenyl radicals with from 1 to 7carbon atoms.
 7. A compound according to claim 1, wherein R₁₀ is analkyl radical with from 1 to 20 carbon atoms.
 8. A compound according toclaim 1, wherein R₂ is an alkyl or alkenyl group from 1 to 7 carbonatoms.
 9. A compound according to claim 1, wherein Y is an alkyleneradical with from 2 to 20 carbon atoms.
 10. A compound according toclaim 1, wherein X is a cycloalkyl-ether, having a ring with 5 or 6members.
 11. A compound according to claim 1, wherein R₁₁ or R₁₂ is analkyl or alkenyl radical with from 1 to 25 carbon atoms.
 12. A compoundaccording to claim 1, wherein R⁷ and R⁸ form, together with the nitrogenatoms to which they are bound, a ring having from 5 to 7 members.
 13. Acompound according to claim 1, wherein the —NR₁₂R₁₃ group is selectedfrom the group consisting of: piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl and hydroxyethylpiperazinyl groups.
 14. A compound accordingto claim 1, wherein R₁₄ is an alkylene radical with from 1 to 10 carbonatoms.
 15. A compound according to claim 1, wherein R₁₅ is an alkyl oralkenyl radical with from 1 to 7 carbon atoms.
 16. A compound accordingto claim 4, wherein R₁ is a saturated or mono-unsaturated alkyl radicalwith from 13 to 15 carbon atoms.
 17. A compound according to claim 5,wherein R₄ is a saturated or mono-unsaturated alkylene radical with from6 to 14 carbon atoms.
 18. A compound according to claim 6, wherein R₇,R₈ and R₉ are methyl groups.
 19. A compound according to claim 9,wherein Y is an alkylene radical with 2 to 6 carbon atoms.
 20. Acompound according to claim 10, wherein the members are selected fromthe group consisting of: tetrahydropyran-2-yl, tetrahydrofuran-2-yl,4-methoxytetrahydropyran-2-yl, and 1,4-dioxan-2-yl.
 21. A compoundaccording to claim 11, wherein R₁₁ or R₁₂ contains from 1 to 5heteroatoms selected from the group consisting of: sulphur, oxygen andnitrogen.
 22. A compound according to claim 12, wherein the ringcontains a further nitrogen atom that is non-substituted or issubstituted by a methyl or ethyl group.
 23. A compound according toclaim 14, wherein R₁₄ is an alkylene radical with from 2 to 4 carbonatoms.
 24. A pharmaceutical composition comprising the compoundaccording to claim and a pharmaceutically acceptable carrier.
 25. Apharmaceutical composition with agonist activity in relation to a CB2cannabinoid receptor comprising the compound according to claim
 24. 26.A cosmetic additive comprising the compound according to claim 1 and acosmetically acceptable carrier.
 27. A method for treating inflammatoryprocesses or inflammatory processes with a hyperalgic component, eachprocess having a neurogenic basis or an immunogenic basis, each basisbeing associated with a immuno-inflammatory condition, aneurodegenerative pathological condition, or a phathological conditionin which an non-psychomimetic effect of cannabinoids mediated either byCB2 receptors or by peripheral CB1 receptors, comprising administering apharmaceutically effective amount of a compound of claim 1.